tbuckley/cabot-search huggingface dataset:
Behavior, Neural Structure, and Metabolism in Adult Male Mice Exposed to Environmentally Relevant Doses of Di(2-ethylhexyl) Phthalate Alone or in a Phthalate Mixture
Authors: Suzanne Ducroq, Eric Duplus, Lucille Penalva-Mousset, Francesca Trivelloni, Aurore L’honoré, Caroline Chabat-Courrède, Ivan Nemazanyy, Valérie Grange-Messent, Isabelle Petropoulos, Sakina Mhaouty-Kodja
Journal: Environmental Health Perspectives (2023)

Background: We have previously shown that chronic exposure of adult male mice to low doses of di(2-ethylhexyl) phthalate (DEHP) altered male sexual behavior and induced down-regulation of the androgen receptor (AR) in the neural circuitry controlling this behavior. Objectives: The cellular mechanisms induced by chronic exposure of adult male mice to low doses of DEHP alone or in an environmental phthalate mixture were studied. Methods: Two-month-old C57BL/6J males were exposed orally for 8 wk to DEHP alone (0, 5, or 50μg/kg/d) or to DEHP (50μg/kg/d) in a phthalate mixture. Behavior, dendritic density per 50-μm length, pre-/postsynaptic markers, synapse ultrastructure, and bioenergetic activity were analyzed. Results: Mice exposed to DEHP either alone or in a phthalate mixture differed in mating, emission of ultrasonic vocalizations, and the ability to attract receptive females in urinary preference tests from control mice. Analyses in the medial preoptic area, the key hypothalamic region involved in male sexual behavior, showed lower dendritic spine density and protein levels of glutamate receptors and differences in other postsynaptic components and presynaptic markers between the treated groups. Ultrastructural observation of dendritic synapses by electron microscopy showed comparable morphology between the treated groups. Metabolic analyses highlighted differences in hypothalamic metabolites of males exposed to DEHP alone or in a phthalate mixture compared to control mice. These differences included lower tryptophan and higher NAD+ levels, respectively, a precursor and end product of the kynurenine pathway of tryptophan metabolism. The protein amounts of the xenobiotic aryl hydrocarbon receptor, one of the targets of this metabolic pathway and known negative regulator of the AR, were higher in the medial preoptic area of exposed male mice. Discussion: Differences in behavior of male mice exposed to environmental doses of phthalates were associated with differences in neural structure and metabolism, with possibly a key role of the kynurenine pathway of tryptophan metabolism in the effects mediated by these substances. https://doi.org/10.1289/EHP11514
Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial
Authors: E. Felip, N. Altorki, C. Zhou, E. Vallières, A. Martínez-Martí, A. Rittmeyer, A. Chella, M. Reck, O. Goloborodko, M. Huang, R. Belleli, V. McNally, M.K. Srivastava, E. Bennett, B.J. Gitlitz, H.A. Wakelee
Journal: Annals of Oncology (2023)

IMpower010 (NCT02486718) demonstrated significantly improved disease-free survival (DFS) with adjuvant atezolizumab versus best supportive care (BSC) following platinum-based chemotherapy in the programmed death-ligand 1 (PD-L1)-positive and all stage II-IIIA non-small-cell lung cancer (NSCLC) populations, at the DFS interim analysis. Results of the first interim analysis of overall survival (OS) are reported here.The design, participants, and primary-endpoint DFS outcomes have been reported for this phase III, open-label, 1 : 1 randomised study of atezolizumab (1200 mg q3w; 16 cycles) versus BSC after adjuvant platinum-based chemotherapy (1-4 cycles) in adults with completely resected stage IB (≥4 cm)-IIIA NSCLC (per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system, 7th edition). Key secondary endpoints included OS in the stage IB-IIIA intent-to-treat (ITT) population and safety in randomised treated patients. The first pre-specified interim analysis of OS was conducted after 251 deaths in the ITT population. Exploratory analyses included OS by baseline PD-L1 expression level (SP263 assay).At a median of 45.3 months' follow-up on 18 April 2022, 127 of 507 patients (25%) in the atezolizumab arm and 124 of 498 (24.9%) in the BSC arm had died. The median OS in the ITT population was not estimable; the stratified hazard ratio (HR) was 0.995 [95% confidence interval (CI) 0.78-1.28]. The stratified OS HRs (95% CI) were 0.95 (0.74-1.24) in the stage II-IIIA (n = 882), 0.71 (0.49-1.03) in the stage II-IIIA PD-L1 tumour cell (TC) ≥1% (n = 476), and 0.43 (95% CI 0.24-0.78) in the stage II-IIIA PD-L1 TC ≥50% (n = 229) populations. Atezolizumab-related adverse event incidences remained unchanged since the previous analysis [grade 3/4 in 53 (10.7%) and grade 5 in 4 (0.8%) of 495 patients, respectively].Although OS remains immature for the ITT population, these data indicate a positive trend favouring atezolizumab in PD-L1 subgroup analyses, primarily driven by the PD-L1 TC ≥50% stage II-IIIA subgroup. No new safety signals were observed after 13 months' additional follow-up. Together, these findings support the positive benefit-risk profile of adjuvant atezolizumab in this setting.
Nanoparticles (NPs)-mediated Siglec15 silencing and macrophage repolarization for enhanced cancer immunotherapy
Authors: Xiaodi Liu, Qi Zhang, Yixia Liang, Shiyu Xiong, Yan Cai, Jincheng Cao, Yanni Xu, Xiaolin Xu, Ye Wu, Qiang Lu, Xiaoding Xu, Baoming Luo
Journal: Acta Pharmaceutica Sinica B (2023)

T cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy. Emerging evidence has shown that interferon-gamma (IFNγ) could enhance CXCL9 secretion from macrophages to recruit T cells, but Siglec15 expressed on TAMs can attenuate T cell proliferation. Therefore, targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues. We herein developed reduction-responsive nanoparticles (NPs) made with poly (disulfide amide) (PDSA) and lipid-poly (ethylene glycol) (lipid-PEG) for systemic delivery of Siglec15 siRNA (siSiglec15) and IFNγ for enhanced cancer immunotherapy. After intravenous administration, these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages (TAMs). With the highly concentrated glutathione (GSH) in the cytoplasm to destroy the nanostructure, the loaded IFNγ and siSiglec15 could be rapidly released, which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation, leading to significant inhibition of hepatocellular carcinoma (HCC) growth when combining with the immune checkpoint inhibitor. The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.
A comprehensive review of protein misfolding disorders, underlying mechanism, clinical diagnosis, and therapeutic strategies
Authors: Shaik Basha, Darshan Chikkanayakanahalli Mukunda, Jackson Rodrigues, Meagan Gail D’Souza, Gireesh Gangadharan, Aparna Ramakrishna Pai, Krishna Kishore Mahato
Journal: Ageing Research Reviews (2023)
KCTD4 interacts with CLIC1 to disrupt calcium homeostasis and promote metastasis in esophageal cancer
Authors: Cancan Zheng, Xiaomei Yu, Taoyang Xu, Zhichao Liu, Zhili Jiang, Jiaojiao Xu, Jing Yang, Guogeng Zhang, Yan He, Han Yang, Xingyuan Shi, Zhigang Li, Jinbao Liu, Wen Wen Xu
Journal: Acta Pharmaceutica Sinica B (2023)

Increasing evidences suggest the important role of calcium homeostasis in hallmarks of cancer, but its function and regulatory network in metastasis remain unclear. A comprehensive investigation of key regulators in cancer metastasis is urgently needed. Transcriptome sequencing (RNA-seq) of primary esophageal squamous cell carcinoma (ESCC) and matched metastatic tissues and a series of gain/loss-of-function experiments identified potassium channel tetramerization domain containing 4 (KCTD4) as a driver of cancer metastasis. KCTD4 expression was found upregulated in metastatic ESCC. High KCTD4 expression is associated with poor prognosis in patients with ESCC and contributes to cancer metastasis in vitro and in vivo. Mechanistically, KCTD4 binds to CLIC1 and disrupts its dimerization, thus increasing intracellular Ca2+ level to enhance NFATc1-dependent fibronectin transcription. KCTD4-induced fibronectin secretion activates fibroblasts in a paracrine manner, which in turn promotes cancer cell invasion via MMP24 signaling as positive feedback. Furthermore, a lead compound K279-0738 significantly suppresses cancer metastasis by targeting the KCTD4‒CLIC1 interaction, providing a potential therapeutic strategy. Taken together, our study not only uncovers KCTD4 as a regulator of calcium homeostasis, but also reveals KCTD4/CLIC1-Ca2+-NFATc1-fibronectin signaling as a novel mechanism of cancer metastasis. These findings validate KCTD4 as a potential prognostic biomarker and therapeutic target for ESCC.
NR5A2/HSD3B1 pathway promotes cellular resistance to second-generation antiandrogen darolutamide
Authors: Masaki Shiota, Miho Ushijima, Shigehiro Tsukahara, Shohei Nagakawa, Leandro Blas, Dai Takamatsu, Satoshi Kobayashi, Takashi Matsumoto, Junichi Inokuchi, Masatoshi Eto
Journal: Drug Resistance Updates (2023)
Endoscopic Appendiceal Orifice Myotomy to Remove an Impacted Appendiceal Fecalith
Authors: Lijuan Mao, Xiaoyun Lu, Qide Zhang
Journal: Clinical Gastroenterology and Hepatology (2023)

A 74-year-old woman with hypertension and diabetes mellitus underwent colonoscopy for intermittent lower abdominal pain for about 3 months. A protruding appendix was noted (Figure A). Computed tomography images demonstrated an oval calcific fecalith located at the appendix (Figure B, red arrow). The patient refused surgery and chose endoscopic therapy. We planned to perform endoscopic appendiceal orifice myotomy (EAOM), similar to endoscopic sphincter myotomy to remove impacted duodenal papillary stones. EAOM was performed with an incision from the top of the appendiceal protruding part to the opening using the Goldknife (Micro-tech, Nanjing, China) with an endoscopic ST hood cap (Figure C). A solution of saline with a small amount of indigo carmine was injected, and the Goldknife was used to deliver water from the tip of the knife and reduce the number of device changes. The fecalith was removed successfully after EAOM (Figure D), with the help of a transparent cap. The incision was closed with 2 hemostatic clips. There were no immediate complications, and the total procedure time was 8 minutes. The patient's abdominal symptoms resolved on the second day after EAOM. The patient was observed in the hospital for a few days, and was discharged uneventfully. No recurrence or any other adverse event was noted during a 2-month follow-up. To our knowledge, this is the first reported use of EAOM for an impacted appendiceal fecalith. eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI5N2E1MmQxMTgzYjI5YjgzMTIzMmRlNTgyMmZkMmIzOCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNzAyMTU1MDA2fQ.ozgmcHPxQtsg9x2sNv_eEqoyQuYwfgp2L9Dg64vFWuIEG1j2kM3wdoUiAur8hPM_xgcvGYpHpVpf7IuMDDoElY927t5ck_DsBomhdfjQqDxyy0bITXDq5ev-q2l8_mWhTlIM8-ynpzsKS1KLPHVcjFQ6xjS94o7Wt7TNk4kvYNePSBIfkZar5SHMZ9xzMyw1FDSzRcNHesX4MmLZ0NyCiJ95MiokmjVZXJj1vVtWaoqfO-GMyo-59S-8x01qV1OkOqn67C_IPhIY3clhP-TxG9V4blxFJ9u5CL-dzHnm_dzWNUSinJHU6syXSe2saq6BAZM14n7yo1q7mVX68Dt4KQ Download .mp4 (33.77 MB) Help with .mp4 files Video
Molecular design of an ultra-strong tissue adhesive hydrogel with tunable multifunctionality
Authors: Yuting Zheng, Avijit Baidya, Nasim Annabi
Journal: Bioactive Materials (2023)

Designing adhesive hydrogels with optimal properties for the treatment of injured tissues is challenging due to the tradeoff between material stiffness and toughness while maintaining adherence to wet tissue surfaces. In most cases, bioadhesives with improved mechanical strength often lack an appropriate elastic compliance, hindering their application for sealing soft, elastic, and dynamic tissues. Here, we present a novel strategy for engineering tissue adhesives in which molecular building blocks are manipulated to allow for precise control and optimization of the various aforementioned properties without any tradeoffs. To introduce tunable mechanical properties and robust tissue adhesion, the hydrogel network presents different modes of covalent and noncovalent interactions using N-hydroxysuccinimide ester (NHS) conjugated alginate (Alg-NHS), poly (ethylene glycol) diacrylate (PEGDA), tannic acid (TA), and Fe3+ ions. Through combining and tuning different molecular interactions and a variety of crosslinking mechanisms, we were able to design an extremely elastic (924%) and tough (4697 kJ/m3) multifunctional hydrogel that could quickly adhere to wet tissue surfaces within 5 s of gentle pressing and deform to support physiological tissue function over time under wet conditions. While Alg-NHS provides covalent bonding with the tissue surfaces, the catechol moieties of TA molecules synergistically adopt a mussel-inspired adhesive mechanism to establish robust adherence to the wet tissue. The strong adhesion of the engineered bioadhesive patch is showcased by its application to rabbit conjunctiva and porcine cornea. Meanwhile, the engineered bioadhesive demonstrated painless detachable characteristics and in vitro biocompatibility. Additionally, due to the molecular interactions between TA and Fe3+, antioxidant and antibacterial properties required to support the wound healing pathways were also highlighted. Overall, by tuning various molecular interactions, we were able to develop a single-hydrogel platform with an "all-in-one" multifunctionality that can address current challenges of engineering hydrogel-based bioadhesives for tissue repair and sealing.
Trajectories in chronic disease accrual and mortality across the lifespan in Wales, UK (2005–2019), by area deprivation profile: linked electronic health records cohort study on 965,905 individuals
Authors: Jane Lyons, Ashley Akbari, Keith R. Abrams, Amaya Azcoaga Lorenzo, Thamer Ba Dhafari, James Chess, Spiros Denaxas, Richard Fry, Chris P. Gale, John Gallacher, Lucy J. Griffiths, Bruce Guthrie, Marlous Hall, Farideh Jalali-najafabadi, Ann John, Clare MacRae, Colin McCowan, Niels Peek, Dermot O’Reilly, James Rafferty, Ronan A. Lyons, Rhiannon K. Owen
Journal: The Lancet Regional Health - Europe (2023)

Understanding and quantifying the differences in disease development in different socioeconomic groups of people across the lifespan is important for planning healthcare and preventive services. The study aimed to measure chronic disease accrual, and examine the differences in time to individual morbidities, multimorbidity, and mortality between socioeconomic groups in Wales, UK.
Reeling from news that reelin defends the brain against Alzheimer’s
Authors: Edmond N. Mouofo, Tara L. Spires-Jones
Journal: Cell Reports Medicine (2023)

In a recent study, Lopera and colleagues investigate a person with extreme resilience to autosomal-dominant familial Alzheimer's disease, which they attribute to a rare variant in the <i>RELN</i> gene encoding reelin.<sup>1</sup>
Socioeconomic Disparities and Mediators for Recurrent Atherosclerotic Cardiovascular Disease Events After a First Myocardial Infarction
Authors: Joel Ohm, Ralf Kuja-Halkola, Anna Warnqvist, Henrike Häbel, Per H. Skoglund, Johan Sundström, Kristina Hambraeus, Tomas Jernberg, Per Svensson
Journal: Circulation (2023)

Low socioeconomic status is associated with worse secondary prevention use and prognosis after myocardial infarction (MI). Actions for health equity improvements warrant identification of risk mediators. Therefore, we assessed mediators of the association between socioeconomic status and first recurrent atherosclerotic cardiovascular disease event (rASCVD) after MI.In this cohort study on 1-year survivors of first-ever MI with Swedish universal health coverage ages 18 to 76 years, individual-level data from SWEDEHEART (Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) and linked national registries was collected from 2006 through 2020. Exposure was socioeconomic status by disposable income quintile (principal proxy), educational level, and marital status. The primary outcome was rASCVD and secondary outcomes were cardiovascular and all-cause mortality. We initially assessed the incremental attenuation of hazard ratios with 95% CIs in sequential multivariable models adding groups of potential mediators (ie, previous risk factors, acute presentation and infarct severity, initial therapies, and secondary prevention). Thereafter, the proportion of excess rASCVD associated with a low income mediated through nonparticipation in cardiac rehabilitation, suboptimal statin management, a cardiometabolic risk profile, persistent smoking, and blood pressure above target after MI were calculated using causal mediation analysis.Among 68 775 participants (73.8% men), 7064 rASCVD occurred during a mean 5.7-year follow-up. Income, adjusted for age, sex, and calendar year, was associated with rASCVD (hazard ratio, 1.63 [95% CI, 1.51-1.76] in the lowest versus highest income quintile). Risk attenuated most by adjustment for previous risk factors and by adding secondary prevention variables for a final model (hazard ratio, 1.38 [95% CI, 1.26-1.51]) in the lowest versus highest income quintile. The proportions of the excess 15-year rASCVD risk in the lowest income quintile mediated through nonparticipation in cardiac rehabilitation, cardiometabolic risk profile, persistent smoking, and poor blood pressure control were 3.3% (95% CI 2.1-4.8), 3.9% (95% CI, 2.9-5.5), 15.2% (95% 9.1-25.7), and 1.0% (95% CI 0.6-1.5), respectively. Risk mediation through optimal statin management was negligible.Nonparticipation in cardiac rehabilitation, a cardiometabolic risk profile, and persistent smoking mediate income-dependent prognosis after MI. In the absence of randomized trials, this causal inference approach may guide decisions to improve health equity.
Toxic Leukoencephalopathy
Authors: Christopher M. Filley, B.K. Kleinschmidt-DeMasters
Journal: New England Journal of Medicine (2001)

Leukoencephalopathy is a structural alteration of cerebral white matter in which myelin suffers the most damage. Toxic leukoencephalopathy may be caused by exposure to a wide variety of agents, including cranial irradiation, therapeutic agents, drugs of abuse, and environmental toxins.1 Toxic leukoencephalopathy particularly involves white-matter tracts devoted to higher cerebral function, causing clinical features that range from inattention, forgetfulness, and changes in personality to dementia, coma, and death. This review focuses on white-matter damage caused by toxins as distinguished from that caused by disorders such as multiple sclerosis, cerebrovascular disease, and metabolic disturbances.2 Although the prevalence of toxic leukoencephalopathy is . . .
A novel rapamycin cream formulation improves facial angiofibromas associated with tuberous sclerosis complex: a double-blind randomized placebo-controlled trial
Authors: Phillip Aitken, Ioana Stanescu, Laura Boddington, Caroline Mahon, Andras Fogarasi, Yi-Hua Liao, Marta Ivars, Ester Moreno-Artero, Doris Trauner, Steven T DeRoos, Jasna Jancic, Milos Nikolic, Patrícia Balážová, Harper N Price, Kinga Hadzsiev, Kate Riney, Stacie Stapleton, Megha M Tollefson, Derek Bauer, Blanka Pinková, Hartley Atkinson
Journal: British Journal of Dermatology (2023)

Abstract Background Facial angiofibromas (FAs) are a major feature of tuberous sclerosis complex (TSC). Topical rapamycin can successfully treat FAs. A new stabilized cream formulation that protects rapamycin from oxidation has been developed in 0.5% and 1% concentrations. Objectives To assess the efficacy and safety of a novel, stabilized topical rapamycin cream formulation. Methods This multicentre double-blind randomized placebo-controlled dose–response phase II/III study with a parallel design included participants aged 6–65 years with FAs of mild or moderate severity according to the Investigator’s Global Assessment (IGA) scale. Participants were randomized to one of three treatment arms: topical rapamycin 0.5%, topical rapamycin 1% or placebo. Treatment was applied once daily for 26 weeks. Safety and efficacy measures were assessed at days 14, 56, 98, 140 and 182. The primary endpoint was the percentage of participants achieving IGA scores of ‘clear’ or ‘almost clear’ after 26 weeks of treatment. Secondary measures included Facial Angiofibroma Severity Index (FASI) and participant- and clinician-reported percentage-based improvement. Safety measures included the incidence of treatment-emergent adverse events and blood rapamycin concentration changes over time. Results Participants (n = 107) were randomized to receive either rapamycin 1% (n = 33), rapamycin 0.5% (n = 36) or placebo (n = 38). All treated participants were included in the final analysis. The percentage of participants with a two-grade IGA improvement was greater in the rapamycin 0.5% treatment group (11%) and rapamycin 1% group (9%) than in the placebo group (5%). However, this was not statistically significant [rapamycin 0.5%: odds ratio (OR) 1.71, 95% confidence interval (CI) 0.36–8.18 (P = 0.50); rapamycin 1%: OR 1.68, 95% CI 0.33–8.40 (P = 0.53)]. There was a statistically significant difference in the proportion of participants treated with rapamycin cream that achieved at least a one-grade improvement in IGA [rapamycin 0.5%: 56% (OR 4.73, 95% CI 1.59–14.10; P = 0.005); rapamycin 1%: 61% (OR 5.14, 95% CI 1.70–15.57; P = 0.004); placebo: 24%]. Skin adverse reactions were more common in patients following rapamycin application (64%) vs. placebo (29%). Conclusions Both rapamycin cream formulations (0.5% and 1%) were well tolerated, and either strength could lead to clinical benefit in the treatment of FA.